Development of lead compounds of a novel class of FtsZ inhibitor compounds to provide an improved treatment for Clostridium difficile infection (CDI) C. difficile is one of the most important causes of health care-associated infections;US annual excess hospital costs have been estimated at $3.2 billion per annum. Current antibacterial therapy disrupts intestinal flora and leaves patients susceptible to recurrences. Whilst a proportion of recurrences may be due to persistent intestinal spores, no current therapy targets sporulation. The transmission and persistence of spores also leads to the inability to prevent CDI in high-risk settings. The hypothesis is that the targeted treatment of both cell division and sporulation by an intestinal-flora sparing agent will provide an innovative and effective therapy, and it is anticipated that this will deliver the added benefits of a reduction in recurrence and transmissibility. Biota's novel FtsZ inhibitor compounds possess potency against C. difficile, including the hypervirulent BI/NAP1/027 strain which now appears to be emerging in wider populations. The compounds are anticipated to target both vegetative clostridial cells as well as clostridial sporulation and are also anticipated to be bacteriocidal, narrow spectrum, and importantly, intestinal flora sparing. In addition, this new class of antibiotic acts by a different mechanism of action to others in development, offering a distinct resistance/cross- resistance profile. Optimization and early development of the lead compounds as outlined in this proposal will be undertaken to enhance the properties necessary to effectively treat CDI. Identification of preclinical candidates will focus primarily on an oral formulation that offers optimal antibacterial activity localized to the gut. Success in this program would offer a development candidate with excellent prospects as an innovative, economical and effective CDI therapy suitable for registration in the U.S. and other countries: a novel, orally delivered, intestinal-flora sparing FtsZ-inhibitor. The predicted targeting of C. difficile cell division and sporulation by this novel antibiotic is anticipated to provide the added benefits of a reduction in recurrence and transmissibility. PUBLIC HEALTH RELEVANCE: This application targets the development of a novel antibiotic for Clostridium difficile infection, one of the most important bacterial health care-associated infections, and a growing problem both in hospitals and in the community in the U.S.